Background: Minimally invasive surgery aims to minimize trauma, cause rapid mobilization, and thus achieve a satisfactory therapeutic result. But the challenging fact with the laparoscopic surgery is its hemodynamic changes because of pneumoperitoneum and the complex visceral pain in the postoperative period. Aim: To find a safe, reliable, and highly effective drug as a premedicant in laparoscopic appendectomies under general anesthesia. Materials and Methods: A total of 110 patients undergoing laparoscopic appendectomies were randomized into two groups: group M (morphine) and group B (buprenorphine) with 55 patients in each group. Group B patients received 0.4 μg of buprenorphine tablet sublingually 1 h before surgery and group M patients received 0.1 mg/kg of intravenous morphine 10 min before anesthesia induction. Intraoperative hemodynamics, postoperative pain score, rescue analgesic requirement, and complications were recorded. Results: Intraoperative vitals that is heart rate and mean arterial pressure were significantly stable in group B compared to group M. Only 11 % patients in group B required dexmedetomidine infusion compared to 37% in group M, to control intraoperative hypertension. Visual analog scale (VAS) values in group B at 2nd (1.30 ± 0.46), 4th (1.31 ± 0.54), and 6th hour (1.33 ± 0.63) were significantly less than group M at 2nd (4.56 ± 0.65), 4th (5.68 ± 0.72), and 6th h (4.45 ± 1.15). Duration of analgesia in postoperative period in group B (260.0 ± 28.52 min) was significantly longer than group M (124.10 ± 20.832 min). Conclusion: Sublingual buprenorphine premedication is an alternative to intravenous injection of morphine with perioperative hemodynamic stability and better postoperative analgesia.

How to cite this article:Vaidiyanathan B, Dhanger S, Raajesh I J. Sublingual buprenorphine versus intravenous morphine as a premedicant and postoperative analgesic in laparoscopic appendectomy under general anesthesia—A randomized control trial. Indian J Pain 2018;32:102-7

The fact that pain after laparoscopic procedures is complex in nature and has unique elements compared to open surgeries, suggests that effective analgesic treatment must be multimodal in nature. Bisgaard[1] suggested a prophylactic multimodal analgesia regimen to reduce postoperative pain consisting of intraoperative short-acting opioids, injection of local anesthetics into the surgical wound, nonsteroidal anti-inflammatory drugs, and dexamethasone. In spite of this multi-pharmacological intervention, postoperative analgesia has not been consistently satisfactory. Intraoperative analgesia is traditionally provided by opioid analgesics.

Laparoscopic surgery has a different pain profile than normal open surgery. Pain during laparoscopic surgery is a result of both somatic and visceral afferents. But intravenous (IV) injection of morphine requires close patient monitoring because of its potential adverse effects such as respiratory depression, hypotension, and gastrointestinal problems.

Buprenorphine is a semisynthetic opioid agonist–antagonist, with an analgesic potency 25–40 times greater than that of morphine sulfate.[2] It has been successfully used for opioid detoxification, cancer-related pain, and postoperative pain control, with a high clinical safety profile and a more prolonged duration of action. Current research and guidelines also state that buprenorphine appears to have a ceiling effect for respiratory depression and not for analgesia.[3] Buprenorphine well absorbs sublingually.[4],[5],[6] The aim of this study was to find the analgesic efficacy and adverse effects of sublingual buprenorphine compared with IV injection of morphine in the acute pain setting.

The primary objective of the study was to find out the efficacy of analgesia in terms of intraoperative hemodynamics. The secondary objectives were visual analog scale (VAS) score in postoperative period, duration of analgesia, defined as the period from the administration of the drug as premedication to the requirement of first rescue analgesia in postoperative period (VAS > 4), total requirement of rescue analgesics, and the side effects of the drug such as sedation, nausea, and vomiting.

Materials and Methods

After obtaining approval from the institutional ethical committee and informed consents from the patients, a total of 110 patients were included in the study (Consort chart [Figure 1]). They were randomized into two groups (55 in each): group M and group B via computer-generated random number sequence. Patients of age group 18–65 years, American Society of Anesthesiology–physical status (ASA-PS) I–II, and ideal body weight more than 50 kg, undergoing elective laparoscopic appendectomy under general anesthesia were included in the study, whereas patients on chronic opioid treatment, hepatic, renal, or cardiac failure, and morbid obesity were excluded from the study.

Patients received tablet ranitidine (150 mg) and alprazolam (0.5 mg) the night before surgery and 2 h before surgery. In the preoperative room, all patients were allocated numbered envelopes containing two buprenorphine tablets (Addnok, 200 μg/tablet, Rusan Lab, Rusan Pharma-Dehradun, India) with a placebo syringe (normal saline) or a syringe with morphine solution (Morphine Sulphate, Neon, Lab-Andheri, Mumbai) and placebo tablets (vitamin C mouth dissolving preparation). The patients were blinded to the content of the solution and tablets. Both the groups received oral premedication and IV injection, 1 h before and 15 min before surgery, respectively, in the preoperative room.

In the operation theatre after attaching standard monitors (electrocardiography [ECG], noninvasive blood pressure, end tidal carbon di oxide (ETCO2), and peripheral oxygen saturation [SpO2]), preoxygenation with 100% oxygen was carried out for 3 min and general anesthesia was induced with injection propofol (2 mg/kg IV) and injection vecuronium (0.12 mg/kg). Endotracheal intubation was performed with appropriate size cuffed endotracheal tube. Anesthesia was maintained with O2: N2O at 50%:50% and isoflurane at 1%. Patients were mechanically ventilated to maintain normocarbia (ETCO2 between 36 and 44 mm Hg). Heart rate (HR), mean arterial pressure (MAP), SpO2, and ETCO2 were recorded at different time intervals such as baseline, 1 min after endotracheal intubation, at the time of skin incision, at the time of initiation of pneumoperitoneum, and then at 15 and 30 min after pneumoperitoneum. Intermittent IV injection of vecuronium was given following assessment of neuromuscular function with train-of-four monitoring. Intraoperative hypotension (mean arterial pressure < 60 mm Hg) was treated with injection mephentermine (6 mg IV) and bradycardia (heart rate < 60 beats/min) was treated with atropine (0.6 mg) intravenously. Supplemental dexmedetomidine bolus (0.2 μg/kg) diluted in 20 mL normal saline was given over 10 min as a loading dose to patients of either group M or B during maintenance of anesthesia, if heart rate or systolic blood pressure level was greater than 20% of baseline.[7] Dexmedetomidine was given only when intraoperative vitals were > 20% of the base line irrespective of the group provided.

It can be a confounding factor for postoperative analgesia but not for the intraoperative hemodynamics. As per our primary objective we recorded the intraoperative hemodynamics and analyzed the requirement of Dexmedetomidine in both the group and we found the hemodynamics were more stable in group B than group M and the requirement of Dexmedetomidine was less in group B than group M.

Mean intra-abdominal pressure (IAP) was maintained below 15 mm Hg throughout the laparoscopic surgery. At the end of the surgery, the residual neuromuscular block was antagonized with neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg IV). Patients were extubated when they were fully awake and shifted to postanesthesia care unit (PACU).

In PACU, patients were monitored for the vitals, the intensity of pain by using 10-point VAS score, and any other postoperative complications. Postoperative injection diclofenac sodium (1.5 mg/kg intramuscular) was used as rescue analgesic, when the VAS score became ≥4, and the total dose of postoperative analgesic was recorded. Respiratory depression was defined as a respiratory rate <10 breaths/min or SpO2 <95% and was treated with oxygen through a venturi mask, fraction of inhalational oxygen > 40%. Injection ondansetron IV with a dose of 8 mg was given in case of vomiting or after two successive episodes of nausea. Postoperative sedation was assessed by Ramsay Sedation Scale.[8]

Sample Size

On the basis of a similar study by Norouzi et al.,[9] we presumed the occurrence of the difference in VAS, 2 h after surgery, among groups to be (2.44 ± 0.82) (mean ± standard deviation [SD]). It was found that total of 55 patients in each group would have been needed to achieve a power of 90% and type 1 error of <0.05. A list of computer-generated random number was created. Statistical analysis was carried out using SPSS software version 16 (SPSS Inc., Chicago, Illinosis, USA). All data were analyzed for normal distribution using the Shapiro–Wilk test. Categorical data were analyzed using the χ2 test or Fisher's exact test as appropriate. Normally distributed parametric data were analyzed using Student's t-test. All tests were two-tailed. P < 0.05 was considered as statistically significant.

Results

We found that the intraoperative hemodynamics and postoperative analgesia were significantly good in buprenorphine group. Both the groups were comparable in demographic profile as shown in [Table 1].

Table 1: Comparison of demographic profile between group M and group B

Two patients in group B had spat the sublingual tablet and one patient in group M was converted to open surgery, therefore they were excluded from the study.

Intraoperative HR and MAP were more stable in group B as compared to group M as shown in [Figure 2]A for HR changes and [Figure 2]B for MAP changes during intubation and during pneumoperitoneum. In group M and group B, 20 patients (37%) and 6 patients (11%) required dexmedetomidine, respectively.

Figure 2: Comparison of heart rate and mean arterial pressure between group M and group B

No significant difference in the Ramsay Sedation Scale score between both the groups in the postoperative period was observed. But 12 patients in group B and 4 patients in group M complained of vomiting and were treated with injection ondansetron (8 mg) intravenously as a single dose.

Discussion

Laparoscopic surgeries are associated with unique hemodynamic changes secondary to pneumoperitoneum and cause complex visceral pain.[10] Various analgesic interventions have been investigated for early pain after laparoscopic surgery. Among all, IV morphine is most commonly used as premedication. Elevated IAP after creation of pneumoperitoneum leads to rise in plasma level of norepinephrine, epinephrine, and renin activities. These physiological changes are of special concern to anesthesiologists for safe and efficient management.

Our study showed that the patients who received buprenorphine as sublingual tablet had less postoperative pain and more stable hemodynamic changes during pneumoperitoneum in laparoscopic surgery as compared to the patients who received IV morphine as premedication.

Buprenorphine has been used in various doses ranging from 5 to 40 μg/kg to supplement anesthesia. Sublingual buprenorphine offers an effective alternative to parenteral route especially in the management of postoperative pain, but only limited studies are available with it as a premedicant.

Intraoperative hemodynamics (changes in HR after intubation, skin incision, and during pneumoperitoneum) were significantly stable in buprenorphine group compared to morphine group. In group M and group B, 20 patients (37%) and 6 patients (11%) required dexmedetomidine, respectively. IV low-dose dexmedetomidine was given as a loading dose (0.2 μg/kg for10 min) as the elimination half-life of the drug was very short (2 h). Sharma and Mehta[11] compared efficacy of two different doses (loading doses of 1 and 0.5 μg/kg) dexmedetomidine on the hemodynamic response to intubation and proved a lower dose is associated with a lesser incidence of adverse effects such as hypotension and bradycardia. The dose used in our study was even less than 0.5 μg/kg.

Cheung et al.[12] studied the effects of intraoperative dexmedetomidine on postoperative pain, with a loading dose of dexmedetomidine 1 μg/kg followed by an infusion of 0.5 μg/kg and proved that there was no morphine-sparing effect in postoperative period. Similarly, McQueen-Shadfar et al.[13] assessed dexmedetomidine infusion on postoperative analgesia in women undergoing major open and laparoscopic gynecologic surgery under general anesthesia and concluded that the administration of dexmedetomidine during laparoscopic cholecystectomy with multimodal analgesia has minimal benefits on the reduction of the postoperative pain score, and for laparoscopic surgery, dexmedetomidine infusion did not provide any analgesic benefit.

In our study, we used dexmedetomidine as a bolus infusion of 0.2 μg/kg during laparoscopic appendectomy and did not observe significant incidence of hypotension or bradycardia, and it was concordant with the study by Dhurjoti Prosad et al.[14]

The intensity of postoperative pain was measured by VAS score at 2nd, 4th, 6th, 12th, 18th, and 24th h after surgery. VAS score was significantly less in buprenorphine group compared to the morphine group. This was concordant with the finding by Norouzi et al.[9]

Cuschieri et al.[15] endorsed that pain scores in those patients receiving regular sublingual buprenorphine for abdominal surgery were consistently less than in those receiving intermittent morphine intramuscularly.

Jalili et al.[16] compared sublingual buprenorphine and IV morphine sulfate in acute bone fracture and found that there was no difference in pain score in both the groups.

Patients in buprenorphine group had a significantly longer duration of postoperative analgesia as compared to morphine group. Akbari et al.[17] compared the efficacy of IV morphine and sublingual buprenorphine for analgesia after lower limb (below the knee) orthopedic surgery and concluded the average pain score and need for meperidine in the buprenorphine group was significantly lower than the morphine group. Our results were comparable with study by Soltani et al.[18] who had compared IV morphine with sublingual buprenorphine in management of postoperative pain after closed reduction orthopedic surgery and found pain score in the morphine group was significantly higher than that in the buprenorphine group with an average score of 2.5 (P < 0.001). Postoperative mean HR in the buprenorphine group was four beats lower than that in the morphine group (P < 0.001) and it was significant.

The results of our study are also comparable with the results by Pugh et al.[19] and Moa and Zetterström.[20] Buprenorphine is slow to dissociate from opioid receptors, which accounts for its long duration of action and remains avidly bound to mu receptors for an extended period and thus maintains adequate analgesia for 8–10 h after sublingual administration.

We found that 12 patients in buprenorphine group and 4 patients in morphine group had complained of post operative nausea and vomiting in first 6 h of surgery and were managed with single dose of the injection ondansetron (8 mg) intravenously. Juhlin-Dannfelt et al.[21] have also found a higher incidence of nausea in sublingual buprenorphine when given for outpatient arthroscopy whereas White et al.,[22] in their review article, have reported with high-level evidence that no difference in incidence of nausea was observed between buprenorphine and morphine.

None of the patients had complained of respiratory insufficiency. Tantucci et al.[23] also suggested that the single dose of sublingual buprenorphine (0.4 mg) does not cause any detrimental respiratory effect because buprenorphine has a better safety profile compared to pure mu agonist opioid with ceiling effect on respiratory depression.

The limitations of our study were that the data were largely drawn from the administration in young patients with weight >50 kg and that the study was confined to laparoscopic appendectomy only. The use of single low-dose dexmedetomidine might be a confounding factor but some of the studies proved that low-dose dexmedetomidine has no effect on postoperative analgesia. Further research with bigger sample is needed in this area.

Conclusion

Sublingual buprenorphine can be used as a safe and effective premedicant in laparoscopic appendectomy with good perioperative hemodynamic stability and less requirement of postoperative analgesics.

Sharma N, Mehta N. Therapeutic efficacy of two different doses of dexmedetomidine on the hemodynamic response to intubation, the intubating conditions, and the effect on the induction dose of propofol: a randomized, double-blind, placebo-controlled study. Anesth Essays Res 2018;12:566-71. [PUBMED] [Full text]